Gastric cytoprotection with heterocyclic sulfonamides

ABSTRACT

The present invention provides a method for gastrointestinal cytoprotection using a class of heterocyclic sulfonamides.

BACKGROUND OF THE INVENTION

The present invention provides a new use of known pharmacologicalagents. In particular, the present invention comprises the use ofcertain heterocyclic sulfonamides for the prophylaxis of certaindiseases of the stomach, the duodenum, and the intestine.

Agents which are useful in the prophylaxis and treatment ofgastrointestinal diseases are sometimes referred to as cytoprotectiveagents. A number of cytoprotective agents are known. U.S. Pat. No.4,097,603 describes the use of certain prostaglandins for gastriccytoprotection. For a brief history of cytoprotection, see Robert,Prostaglandins (supplement) 2: 89-96 (1981).

PRIOR ART

Gastric cytoprotection methods are disclosed, for example, in U.S. Pat.No. 4,083,998 (Robert, "Treatment of Inflammatory Disease of theMammalian Large Intestine with Cytoprotective Prostaglandins"), issuedApr. 11, 1978, U.S. Pat. No. 4,081,553 (Robert, "CytoprotectiveProstaglandins for Use in Intestinal Diseases"), issued Mar. 28, 1978;U.S. Pat. No. 4,097,603 (Robert, "Gastric Cytoprotection withNon-Antisecretory Doses of Prostaglandins"), issued June 27, 1978; andU.S. Pat. No. 3,917,828 (Robert, "Method of Reducing the UndesirableGastrointestinal Effects of Prostaglandin Synthetase Inhibitors"),issued Nov. 4, 1975.

The compounds disclosed herein as cytoprotective agents have beendisclosed as carbonic anhydrase inhibitors and as diuretics in U.S. Pat.Nos. 2,554,816 and 2,868,800.

Certain prostaglandins and prostaglandin analogs have been found usefulin reducing gastric secretion and thus treating or preventing gastric orduodenal ulcers. See, e.g., U.S. Pat. Nos. 3,903,297 and 3,781,429. Theprevention of gastric and duodenal erosive diseases (e.g., gastric andduodenal ulceration and erosive gastritis) with antacid or gastricantisecretory agents other than prostaglandins is likewise known in theart. See, for example, Mann, et al., Gastroenterology 68: A-88/945(1975) which describes the use of metiamide (a gastric antisecretoryagent) in preventing the gastric damage caused by the treatment of ratswith aspirin and bile. See further, Mann, Gastroenterology 68: A-89/946(1976) which describes the prevention of acute erosive gastritis byantacid administration.

However, gastric cytoprotection is different from gastric antisecretionand is an important pharmacological property. See, e.g., Robert, U.S.Pat. No. 4,097,603, "Gastric Cytoprotection with Non-antisecretory Dosesof Prostaglandins"; Robert, "Cytoprotection by Prostaglandins,"Gastroenterology 77: 761-767 (1979); and Robert, et al., "Cytoprotectionby Prostaglandins in Rats," Gastroenterology 77: 433-443 (1979).

SUMMARY OF THE INVENTION

The present invention comprises a method of preventing agastrointestinal disease in a mammal with high susceptibility to theacquisition of said disease, which comprises:

administering to said mammal systemically an amount effective to preventthe development of said disease of a cytoprotective heterocyclicsulfonamide.

The present invention further provides a method of preventing agastrointestinal disease in a mammal with high susceptibility to theacquisition of said disease, which comprises:

administering to said mammal systemically an amount effective to preventthe development of said disease of a compound selected from the groupconsisting of

N-methyl-2-benzothiazolesulfonamide;

5-(2-methylpropionamido)-1,3,4-thiadiazole-2-sulfonamide;

5-acetamido-1,3,4-thiadiazole-2-sulfonamide; and

6-ethoxy-2-benzothiazolesulfonamide.

5-Acetamido-1,3,4-thiadiazole-2-sulfonamide, or acetazolamide ismarketed under the trade name Diamox® as a diuretic.6-Ethoxy-2-benzothiazolesulfonamide (ethoxzolamide) was marketed as adiuretic under the trade name Cardrase®. These compounds are alsocarbonic anhydrase inhibitors. Carbonic anhydrase is an enzyme presentin the gastric mucosa. It is involved in the secretion of acid by thestomach. At the same time that acid is secreted into the lumen, an equalamount of bicarbonate is formed by the cells and enters the blood. Bygiving an inhibitor of carbonic anhydrase, acid secretion as well asbicarbonate formation are reduced. However, a reduction in acidsecretion is not involved in cytoprotection, since other inhibitors ofacid secretion, such as histamine H₂ blockers (cimetidine),anticholinergic agents (methscopolamine bromide) as well as antacids (pH7 buffer) are not cytoprotective. See Robert et al., Gastroenterology77: 433-443 (1979).

Kollberg, et al., Scand. J. Gastroenterol. 16: 385-387, 1981, disclosesthat injections of acetazolamide sensitized the gastric mucosa of ratsto the damaging effect of indomethacin. The size of mucosal lesionsproduced by indomethacin was increased by acetazolamide. Thus, one wouldhave expected acetazolamide to be anticytoprotective. The fact that itis cytoprotective is surprising and unexpected.

By "cytoprotective heterocyclic sulfonamide" is meant any sulfonamide ofthe formula X-SO₂ NR₁ R₂, wherein R₁ and R₂ are the same or differentand are hydrogen, alkyl, alkaryl, and aryl and X is a substituted orunsubstituted heterocyclic moiety selected from the group consisting oftriazole, thiadiazole, tetrazole, pyridotriazole, and benzothiazole,which reduces gastric lesions in the rat when administered in apharmacologically practical amount in the test system described in theExample below.

The present invention includes the treatment of each of the variousmammalian species, especially humans. With respect to nonhumans, thepresent invention is particularly and especially concerned with treatingdomesticated animals, for example, cattle, dogs, cats, and swine.

Any convenient route of administration is employed. Thus, oralformulation and oral administration is, for example, the preferred routefor use in humans although parenteral (e.g., intravenous,intraperitoneal, and intramuscular) administration is also employed.

When these compounds are administered orally, they are formulated astablets, capsules, or as liquid preparations, with the usualpharmaceutical carriers, binders, and the like. For parenteraladministration, pharmaceutically acceptable sterile suspensions orsolutions are preferred.

With respect to the method described above, gastric and intestinalinflammatory diseases include specifically gastric ulcer, duodenal ulcerand gastritis, although other gastric inflammatory conditions, such asthose secondary to radiation exposure, are likewise included within itspurview. See U.S. Pat. No. 4,88,784 for a description of these sourcesof radiation for which the present invention provides cytoprotection.Gastrointestinal diseases caused by exposure to noxious chemical agentsare also treated by the method of the present invention. Also includedwithin the term "gastrointestinal diseases" which are prevented by themethod of the present invention are the undesirable side effectsproduced by the administration of non-steroidal antiinflammatory (NOSAC)agents (which are prostaglandin synthetase inhibitors), as described inU.S. Pat. No. 3,917,828.

A further aspect of the present invention resides in the selection ofpatients for the present method who exhibit a high susceptibility to theacquisition of gastrointestinal inflammatory diseases. In accordancewith the invention, patients who will benefit from these gastriccytoprotective compounds will fall into several classes. First, patientswith a previous history of gastric or duodenal ulcer are known to behighly susceptible to a recurrence of this disease, and thus the presentinvention provides a method for preventing or reducing recidivism insuch ulcer-prone patients. Moreover, those with two or more episodes ofgastric or duodenal ulcer, being particularly susceptible to therecurrence of gastric inflammatory diseases, are especially contemplatedas subjects for the chronic administration of the gastric cytoprotectiveprostaglandins of the present invention.

A further class of subjects which exhibit a high susceptibility to theacquisition of gastrointestinal inflammatory disease are thoseexperiencing stressful environmental conditions, whether of physical oremotional origin. Such subjects particularly include those persons whoseemotional disposition has been identified as a source of recurrentgastritis or a prior episode of gastric or duodenal ulcer disease. Othersuch subjects include patients under severe physical conditions such asshock, sepsis, burns, multiple fractures, accident injuries with trauma(head, chest, abdomen, etc.), hemorrhage, extensive and prolongedsurgical interventions, and organ transplants.

Further, patients for whom treatment by the present method is indicatedinclude persons exhibiting chronic and excessive ethanol consumption. Inparticular, the use of the present method by persons diagnosed asalcoholics, according to standard methods for the diagnosis of thisdisease, are contemplated by the present method. Especially suitablecandidates for the present method are those alcoholics with a history ofrecurrent or persistent gastritis resulting from uncontrolled oruncontrollable consumption of ethanol.

Further included as suitable subjects for treatment by the presentmethod are humans exhibiting acute exposure to cytodestructive doses ofionizing radiations. While ionizing radiation from any source iscontemplated, particularly suitable subjects include patients exposedaccidentally to high levels of radiation and those receiving measureddoses of radiation for therapeutic reasons (e.g., in the treatment ofneoplastic diseases). Cytodestructive doses of such radiation are thosecapable of producing the symptoms of gastrointestinal distressassociated with radiation sickness.

Further included as suitable subjects for treatment by the presentmethod are humans exhibiting acute or chronic ingestive exposure ofnoxious, gastrointestinal cytodestructive or gastrointestinal cytotoxicchemical agents. Particularly contemplated by the present invention arethose persons who suffer an accidental, acute exposure to poisons orother agents which are noxious or erosive to the gastrointestinaltissues. For example, children who ingest household chemicals, such asdetergents, drain cleaners, and the like, are suitable subjects fortreatment by the present method. In such an instance treatment isinitiated following the usual emergency procedures, if any, which areindicated to control the systemic effects resulting from the ingestedpoison. Further included as suitable subjects for the present inventionare those persons whose exposure to noxious gastrointestinalcytodestructive or gastrointestinal cytotoxic chemical agents is of amore chronic nature. For example, those persons whose occupationrequires them to formulate or apply agricultural poisons (e.g.,pesticides and herbicides) likewise are subjects for the presentinvention. In particular, such persons who are chronically exposed tothese chemical agents and such chronic exposure has resulted in at leasta single episode of gastritis or gastric or duodenal ulcer resultingtherefrom are especially suitable for treatment in accordance with thepresent method. Further, humans exposed to therapeutic doses ofchemotherapeutic agents used in the treatment of neoplastic diseaseswith known gastrointestinal cytotoxic or cytotoxic side effects providefurther subjects for the present method.

Further included as suitable subjects for treatment by the presentmethod are humans being treated with NOSAC such as aspirin,indomethacin, phenylbutazone, mefenamic acid, flufenamic acid, naproxen,2-phenoxyphenylpropionic acid,(+)-3-chloro-4-cyclohexyl-α-methylphenylacetic acid, and ibuprofen.

Finally, the present invention is employed in subjects exhibiting arecent exposure to pathogens capable of producing diseases characterizedby untoward gastric symptoms such as vomiting. Specifically contemplatedby this application of the present invention are those persons who intravelling to foreign countries are likely to encounter or haveencountered pathogens which have produced gastro-intestinal distress,and for whom a further exposure is contemplated.

The present invention requires administration of a dose of the compoundeffective to prevent the development of the gastrointestinalinflammatory disease. Thus, the dose required in accordance with thepresent invention is sufficiently great so as to permit thecytoprotective effect, but much smaller than those doses capable ofproducing any significant other effects.

The dosage regimen for the use of these compounds in accordance withthis invention will depend on a variety of factors, including the type,age, weight, sex, and medical condition of the mammal, the nature andseverity of the gastrointestinal disease and the particular compound tobe administered. It is within the skill of the attending physician orveterinarian to determine the patient's susceptibility to the gastricdisease, and to prescribe an effective amount of the heterocyclicsulfonamide compound. In doing that, the physician or veterinarian wouldby one method start at a relatively low dose of the compound, forexample, about 1 mg/kg/day to about 50 mg/kg/day, and observe theresponse of the patient for a few days. The dose is then adjusteddownward or upward if necessary until the optimum effective dose isfound. For example, the maximum needed dose is usually between about 1mg/kg/day and about 100 mg/kg/day although it may be necessary tooccasionally exceed these doses when the susceptibility to thegastrointestinal disease is especially severe. Once the minimumeffective dose of the particular heterocyclic sulfonamide compound isdetermined for a particular subject, it is advantageous to provide thesubject with the dosage schedule which will provide a substantiallyuniform level of the compound.

The most preferred compound of the present invention is acetazolamide.

The preparation of the compounds used in the methods of the presentinvention is described in U.S. Pat. Nos. 2,554,816 and 2,868,800 notedabove. An improved method for preparing some of these compounds isdescribed in U.S. Pat. No. 2,980,679. The preparations of such compoundsfrom these patents are incorporated by reference herein.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The efficacy of the compounds of the present invention asgastrointestinal cytoprotection agents is seen by the Example givenbelow.

EXAMPLE

Female rats of an average body weight of 210 g were fasted for 24 hr.They were also deprived of water during the overnight period (from 3p.m.), and placed in individual cylindrical stainless steel cages toprevent coprophagy. On the following morning they were given 1.5 ml ofvarious compounds orally at a dose of 50 mg/kg.

The compounds were shaken overnight in water containing polysorbate 80to obtain a fine suspension (one drop per 20 ml). Thirty minutes aftertreatment, 1 ml of absolute ethanol was given orally and the animalswere killed with CO₂ 1 hr after the ethanol administration. Theirstomachs were dissected out, opened along the greater curvature andrandomized so that the examiner had no knowledge of the treatment given.They were examined with a 2X binocular magnifier for the presence ofnecrotic lesions. The number of nacrotic lesions per stomach wasrecorded and the average number per group was calculated. Results wereexpressed as the number of gastric lesions as compared to the control.The Dunnett two-tailed t-test (see Dunnett, "A Multiple ComparisonProcedure for Comparing Several Treatments with Control," Amer. Stat.Assoc. 50:1096-1121 (1955)) was used for statistical analysis.

Compounds of this invention showing a statistically significant decreasein necrotic lesions are set forth in Table 1. A similar effect is shownfor ethoxzolamide (6-ethoxy-2-benzothiazolesulfonamide-Cardrase®) inTable 2.

                  TABLE 1                                                         ______________________________________                                                                No. of lesions                                        Name of Compound        (Mean)                                                ______________________________________                                        Vehicle only (control)  12.3                                                  N--methyl-2-benzothiazolesulfonamide                                                                  6.3                                                   5-(2-methylpropionamido)-1,3,4-thiadiazole-2-                                                         7.0                                                   sulfonamide                                                                   5-acetamido-1,3,4-thiadiazole-2-sulfonamide                                                           6.8                                                   (acetazolamide)                                                               ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        No. of lesions                                                                Name of Compound       (Mean)                                                 ______________________________________                                        Vehicle                15.9                                                   6-ethoxy-2-benzothiazolesulfonamide                                                                  7.4                                                    (ethoxzolamide)                                                               ______________________________________                                    

I claim:
 1. A method of preventing a gastrointestinal inflammatory disease in a mammal with high susceptibility to the acquisition of said disease, which comprises:administering to said mammal systemically an amount effective to prevent the development of said disease of a compound selected from the group consisting of N-methyl-2-benzothiazolesulfonamide; 5-(2-methylpropionamido)-1,3,4-thiadiazole-2-sulfonamide; 5-acetamido-1,3,4-thiadiazole-2-sulfonamide; and 6-ethoxy-2-benzothiazolesulfonamide.
 2. A method of claim 1, wherein said mammal is a human.
 3. A method of claim 2 wherein the compound is 5-acetamido-1,3,4-thiadiazole-2-sulfonamide (acetazolamide).
 4. A method of claim 2 wherein the compound is 6-ethoxy-2-benzothiazolesulfonamide (ethoxzolamide).
 5. A method of claim 2, wherein the compound is N-methyl-2-benzothiazolesulfonamide.
 6. A method of claim 2, wherein the compound is 5-(2-methylpropionamido)-1,3,4-thiadiazole-2-sulfonamide; 